Two large studies offer reassurance, but patients should still be warned of cleft palate risk.
Prescription opioids or macrolide antibiotics during pregnancy don’t significantly increase the risk of major birth defects, according to two new large studies.
But children were still slightly more likely to have an oral cleft if the mother had taken opioids, highlighting the need for cautious prescribing during pregnancy, said an independent expert.
Multiple studies have looked at the safety of both macrolide and antibiotic use in pregnancy, but the results have been conflicting.
Last year, a UK study of more than 100,000 children found a small uptick in major malformations among those children whose mother had taken penicillin or a macrolide during pregnancy. These researchers determined that mothers who took erythromycin, clarithromycin or azithromycin had a child with a major malformation at a rate of 27.7 per 1000, compared with 17.7 per 1000 for those who took penicillin.
The work prompted calls for a review of the TGA classification and raised concerns for the treatment of chlamydia and pertussis, since all major guidelines recommended azithromycin.
Now, the BMJ has published a nation-wide registry study by Danish authors seeking to confirm those UK findings in an independent population.
The new study involved almost 1.2 million live birth pregnancies, including pregnancies during which penicillin was taken as well as those where one of five macrolides (azithromycin, clarithromycin, erythromycin, roxithromycin, and spiramycin) was used.
The authors found no significant difference in rates of major birth defects between the macrolide and penicillin groups (35.1 cases vs 37 per 1000). In addition, none of the macrolides taken during the first trimester were found to be associated with an increased risk of major birth defects.
The authors suggested the difference in findings may be partly due to probability sampling in the UK cohort vs nationwide data. All birth defect diagnoses are automatically recorded in Danish registries, compared to the UK study relying on manual collection by GPs when children are three years old.
“We believe that our data provide reassurance about the risk of major birth defects when treatment with macrolide antibiotics is needed during pregnancy. Our findings could help inform clinicians, patients and drug regulatory authorities,” the authors wrote.
GP Dr Wendy Burton told TMR the study looked robust and the results were reassuring in contrast to previous studies on macrolides.
“[This study] demonstrates the power of large, well regulated, organised databases. Twenty years of national data cross referenced to hospital diagnosis and filled prescription data was able to give us larger numbers for comparison than the earlier BMJ study,” said Dr Burton, who is chair of the RACGP Antenatal/Postnatal Care Specific Interests network.
“Based on this larger data set, I would feel more comfortable about prescribing a macrolide in the first trimester.”
Yet despite the reassuring data, Dr Burton said it was wise to be circumspect with prescriptions.
“I think we must always be cautious when prescribing in pregnancy, particularly in the first trimester,” she said.
“The principles must always be to only use medication if the indication is clear and then to use the safest known medication for the shortest period of time.”
The evidence on opioid teratogenicity has been similarly limited and conflicting.
The second new study drew on the records of approximately 2.7 million pregnant women in the US. The authors looked for an association between major birth defects and cases where two or more scripts of any opioid were dispensed in the first trimester.
They focussed on the types of malformations that had previously been associated with opioid exposure, including cardiovascular malformations such as ventricular septal defect/atrial septal defect, spina bifida, oral cleft, and clubfoot.
“Prescription opioids used in early pregnancy are not associated with a substantial increase in risk for most of the malformation types considered,” they wrote.
However, they said it was concerning that opioid use was linked to a small increase in risk of oral clefts, and cleft palate in particular.
“This increase in risk [for cleft palate] corresponds to four to five additional cases of cleft palate per 10,000 pregnancies exposed to opioids in the first trimester,” they wrote, adding that clinicians needed to be aware of this risk and counsel patients appropriately.
